Role of adenosine A3 receptor in suppressing prostate cancer

腺苷A3受体在抑制前列腺癌中的作用

基本信息

批准号：
7516278
负责人：
Vickram Ramkumar
金额：
$ 21.83万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-13 至 2011-08-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7516278
关键词：
ADORA3 gene Adenosine Adenosine A3 Receptor Adverse effects Agonist Androgens Animals Antifungal Agents Antineoplastic Agents Applications Grants Cell Proliferation Cells Cessation of life Chemicals Class Complement Factor B Conjugated Estrogens Count Cyclic AMP-Dependent Protein Kinases Data Disease Disease regression Dose Drug usage Estrogens Extracellular Signal Regulated Kinases Frequencies Gelatinase A Gelatinase B Gene Expression Generations Goals Human Cell Line Injection of therapeutic agent Intraperitoneal Injections Ketoconazole Kidney Failure Laboratories Left Lesion Localized Lung Malignant neoplasm of prostate Mediating Membrane Metastatic Prostate Cancer Metastatic to Methods Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinases Mitogens N(6)-(3-iodobenzyl)-5&apos -N-methylcarboxamidoadenosine NADPH Oxidase Neoplasm Metastasis Nuclear Nucleosides Numbers Oxides Pathway interactions Pharmaceutical Preparations Phenotype Phosphorylation Platinum Process Proteins Public Health Rattus Reactive Oxygen Species Regulation Research Role SCID Mice Schedule Severe Combined Immunodeficiency Signal Pathway Source Superoxides System Testing Time Transcription Factor AP-1 Treatment Effectiveness Treatment Protocols Vascular Endothelial Growth Factors Week Withdrawal base cancer cell cell motility chemotherapeutic agent cytochrome b558 day docetaxel enzyme activity hearing impairment human CYBA protein immunodeficient mouse model intravenous injection link protein migration mortality novel protein expression transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer metastasis is a serious sequelae of prostate cancer, associated with increased mortality and reduces treatment effectiveness. Androgen withdrawal therapy, the hallmark of treatment promotes tumor regression. However, treatment benefits wane after an average of 18-24 months, necessitating the use of second-line agents. Chemotherapeutic agents though effective, are not curative and there is an urgent need for novel therapies to be initiated early in the course of the disease. Our laboratory has recently shown that activation of the adenosine A3 receptor (A3AR) subtype inhibits prostate cancer cell proliferation and metastasis in rat and human cell lines of androgen-independent metastatic prostate cancer and in SCID mice injected with the AT6.1 rat metastatic prostate cancer line. The "metastatic phenotype" is mediated in part through the generation of high levels of ROS by these cells via the NADPH oxidase system, which activates signaling pathways, such as nuclear factor (NF)-:B and extracellular signal regulated kinase (ERK) mitogen activated protein (MAP) kinase/activator protein (AP-1) transcription factor. Through these mechanisms, ROS positively regulates the expression of proteins linked to the metastatic phenotype. In this proposal, we will test the hypothesis that activation of the A3AR inhibits the NADPH oxidase activity and thereby suppresses downstream signaling pathways, primarily ERK1/2 MAP kinase and NF-:B and metastatic gene expression regulated by ROS. In a severe combined immunodeficient (SCID) mouse model, we will determine the optimal A3AR treatment protocol to effect maximum inhibition of metastasis. The specific goals are: (1) To determine the optimal treatment parameters for using A3AR agonist to reduce prostate cancer metastasis, focusing on optimal doses and treatment schedules and also determining whether these agonists are effective following establishment of cell metastasis. (2) To determine the mechanism(s) by which the A3AR inhibits ROS generation and motility and metastasis of prostate cancer cells. We will focus on NADPH oxidase and determine the mechanism(s) underlying its activation and subunit expression via the ERK1/2 MAP kinase/AP-1 and NF-:B pathways. Overall, these studies will provide novel information concerning the efficacy of and mechanism underlying the anti-metastatic actions of A3AR agonists in prostate cancer and provide a rational basis for using this class of drug clinically. PUBLIC HEALTH RELEVANCE: Prostate cancer metastasis is a serious consequence of prostate cancer, which if left untreated, could result in death. Several treatment options exist, such as androgen withdrawal therapy and the use of drugs such as ketoconazole and Premarin. In addition, certain platinum-based anti-cancer agents are also effective against the disease but do produce significant side effects such as hearing loss and kidney failure. Overall, such treatments are not curative and there is an urgent need for novel therapies early in the course of the disease. We have shown that a compound which mimics an endogenous chemical in the body, adenosine, can reduce the metastasis of prostate cancer to the lung. However, we do not know how this beneficial action is produced. In addition, we would like to optimize the drug treatment to produce more reductions in lung metastasis. Therefore, these goals will form the specific aims of the current grant proposal. We believe that this study could uncover a novel method of treating prostate cancer metastasis.

描述（由申请人提供）：前列腺癌转移是前列腺癌的严重后遗症，与死亡率增加和治疗效果降低相关。雄激素戒断疗法是促进肿瘤消退的治疗标志。然而，治疗效果平均在 18-24 个月后就会减弱，因此需要使用二线药物。化疗药物虽然有效，但不能治愈，迫切需要在病程早期启动新疗法。我们的实验室最近表明，在雄激素非依赖性转移性前列腺癌的大鼠和人类细胞系以及注射 AT6.1 大鼠转移性前列腺癌的 SCID 小鼠中，腺苷 A3 受体 (A3AR) 亚型的激活可抑制前列腺癌细胞的增殖和转移线。 “转移表型”部分是通过这些细胞通过 NADPH 氧化酶系统产生高水平的 ROS 介导的，该系统激活信号通路，例如核因子 (NF)-:B 和细胞外信号调节激酶 (ERK) 丝裂原活化蛋白（MAP）激酶/激活蛋白（AP-1）转录因子。通过这些机制，ROS 积极调节与转移表型相关的蛋白质的表达。在本提案中，我们将测试以下假设：A3AR 的激活会抑制 NADPH 氧化酶活性，从而抑制下游信号通路，主要是 ERK1/2 MAP 激酶和 NF-:B 以及 ROS 调节的转移基因表达。在严重联合免疫缺陷 (SCID) 小鼠模型中，我们将确定最佳的 A3AR 治疗方案，以最大程度地抑制转移。具体目标是：（1）确定使用A3AR激动剂减少前列腺癌转移的最佳治疗参数，重点关注最佳剂量和治疗方案，并确定这些激动剂在细胞转移建立后是否有效。 (2)确定A3AR抑制前列腺癌细胞ROS产生、运动和转移的机制。我们将重点关注 NADPH 氧化酶，并通过 ERK1/2 MAP 激酶/AP-1 和 NF-:B 途径确定其激活和亚基表达的机制。总体而言，这些研究将为A3AR激动剂在前列腺癌中的抗转移作用的功效和机制提供新的信息，并为临床使用此类药物提供合理的基础。公共卫生相关性：前列腺癌转移是前列腺癌的严重后果，如果不及时治疗，可能会导致死亡。存在多种治疗选择，例如雄激素戒断疗法和使用酮康唑和倍美力等药物。此外，某些铂类抗癌药物也能有效对抗这种疾病，但确实会产生明显的副作用，例如听力损失和肾衰竭。总体而言，此类治疗无法治愈，并且在病程早期迫切需要新的治疗方法。我们已经证明，一种模仿体内内源性化学物质腺苷的化合物可以减少前列腺癌向肺部的转移。然而，我们不知道这种有益作用是如何产生的。此外，我们希望优化药物治疗，以进一步减少肺转移。因此，这些目标将构成当前拨款提案的具体目标。我们相信这项研究可以揭示一种治疗前列腺癌转移的新方法。